Abnormalities of the heart rhythm remain a major public health threat and the treatment of cardiac arrhythmias is a strict challenge to the physician. We plan to continue our investigations into the passive and active membrane properties of heart cells that determine normal and abnormal excitability including those types which underly the development of cardiac arrythmias. Moreover, we will continue to investigate the effects that antiarrhythmic drugs have on the determinants of excitability in normal and abnormal cardiac tissues. The multiple microelectrode techniques of intracellular current application and voltage clamping are used in cardiac Purkinje fibers and permit the selective control of numerous electrophysiologic variables which, in turn, allows the direct assessment of many active and passive membrane properties relevant to cardiac excitability. These include ionic conductances, active generator properties, cable properties, and current-voltage relationships. In the past, a major limitation in assessing excitability was the inability to determine intracellular ionic activities which are of importance in establishing the driving force for ionic species. We are now using ion-sensitive microelectrodes to measure ionic activities. We also developed a computer based data analysis system that allows us to track alterations in the determinants of excitability in time after an intervention. The first years of the grant demonstrated the power of these methods to elucidate fundamental mechanisms by which arrhythmogenic intervensions and antiarrhythmic drugs work, and the investigations have seriously questioned much of the earlier literature. This renewal proposes to further define the components of excitability by these improved techniques in normal and abnormal tissues. The latter will result from altering the physiologic or pharmacologic environment of the tissue by using toxic metabolites that accumulate in the ischemic heart, and by changing the po2 ionic milium and pH. The effects of antiarrhythmic drugs on these alterations will also be investigated. As was true for the first years of this grant, we anticipate that the renewal will further extend our understanding of the actions of antiarrhythmic drugs. We plan to continue developing classifications of arrhythmogenesis and anti-arrhythmic drugs based on our fundamental findings that are electrophysiologically sound and clinically useful.